The present application claims benefit of priority to U.S. Provisional Application Ser. No. 60/653,823, filed Feb. 17, 2005, the entire contents of which are hereby incorporated by reference.
The U.S. Government own rights in this invention pursuant to grant number AI58740 from NIH and merit grants awarded to Jack Stapleton and Jinhua Xiang from the Veterans Administration.
I. Field of the Invention
The present invention relates generally to the fields of molecular biology and virology. More particularly, it concerns methods and compositions to treat, inhibit or prevent HIV infection.
II. Description of Related Art
A. GB Virus Type C
GB virus type C (GBV-C), also known as hepatitis G virus (HGV), is a virus whose genomic organization and nucleotide sequence places it in the Flavivirus family (Robertson et al., 1998). It is the most closely related human virus to hepatitis C virus (HCV) (Leary et al., 1996; Linnen et al., 1996; Simons et al., 1995). It has been suggested that these viruses should be classified together with non-human GB-hepatitis agents as the hepacivirus genus. Although GBV-C was originally associated with post-transfusion hepatitis in humans (Linnen et al., 1996), subsequent epidemiological studies indicated that it does not cause acute or chronic hepatitis (Alter et al., 1997a; Alter et al., 1997b). In addition, experimental GBV-C infection of chimpanzees was not associated with acute hepatitis (Bukh et al., 1998).
Persistent GBV-C viremia (as detected by RT-PCR) is common, with 0.9% to 3% of healthy U.S. blood donors and approximately 20%-30% of patients with HCV infection persistently infected with GBV-C (Dawson et al., 1996; Feucht et al., 1997; Simons et al., 1995a; Simons et al., 1995b; Tacke et al., 1997). Following infection, about 80% of people clear their viremia, concomitantly developing antibody to the GBV-C E2 protein (Feucht et al., 1997; Thomas et al., 1998). Thus, it is estimated that approximately 20% of infected people remain viremic for long periods of time. GBV-C appears to be transmitted primarily by parenteral exposure (Simons et al., 1995), although there are data suggesting that sexual and/or household transmission of GBV-C infection may occur (Akiyoshi et al., 1999; de Martino et al., 1998; Nerurkar et al., 1998; Tanaka et al., 1997; Wu et al., 1997).
B. GBV-C and HIV
During progressive human immunodeficiency virus type 1 (HIV-1) infection, the virus-specific immune responses of an infected subject gradually deteriorate, leading to the development of acquired immunodeficiency syndrome (AIDS). Most infected patients do not exhibit overt clinical manifestations of the disease for six to ten years following initial infection, however, most individuals infected with HIV eventually die from conditions or infections; that the individual's immune system is no longer equipped to fight. While treatment for AIDS has been forthcoming, no effective cure has been reported. Thus, preventative and treatment options against HIV infection and the development of AIDS remain highly desirable.
GBV-C has been investigated in the context of HIV infection. The course of HIV-1 infection is extremely variable among infected individuals, although the reasons for this observation are not fully understood. Individuals whose HIV disease progresses slowly are often called long-term non-progressors (LTNPs). The prevalence of LTNPs varies from 1% to 25% of infected people, depending upon the definition used (reviewed in Easterbrook, 1999). There are no specific clinical criteria for LTNP. However, non-progression generally implies the absence of HIV-related clinical disease 10 or more years following infection and an absolute CD4 count of ≧500 cells/mm3 (Easterbrook, 1999). Evaluation of LTNP's has identified HIV isolates with deletions in key replicative genes (Deacon et al., 1995) and host genetic factors, including specific HLA haplotypes (reviewed in reference Rowland-Jones, 1999). In some individuals, polymorphisms that result in absent or reduced expression of HIV co-receptors have been identified (Huang et al., 1996). However, these findings are uncommon and thought to account for no more than one-third of LTNP's (Rowland-Jones, 1999).
Persistent GBV-C infection is common in humans, with infection rates of approximately 0.9% to 3% in healthy blood donors, 20-30% in HCV-positive people (Dawson et al., 1996), and 35%-40% in HIV-positive individuals. GBV-C infection can persist for decades in the absence of any clinical morbidity or mortality. Among immune-competent individuals, it is estimated that 60% to 75% of GBV-C-infected people clear the infection, concomitantly developing antibodies to the envelope glycoprotein E2 (Thomas et al., 1998). It is also known that GBV-C can be propagated in cultures of peripheral blood mononuclear cells (PBMC's) (Fogeda et al., 1999).
In 1998, Toyoda et al. found that hemophiliacs co-infected with HIV and GBV-C had a lower plasma HIV RNA concentration and a lower incidence of AIDS diagnoses compared to those infected with HIV alone (Toyoda et al., 1998), although the differences were not statistically significant. In contrast, Sabin and colleagues found an increased rate of AIDS and death in hemophiliacs “exposed” to GBV-C (Sabin et al., 1998) compared to non-exposed individuals. This study included HIV-positive subjects who were either GBV-C viremic as determined by detection of GBV-C RNA in plasma, or HIV-infected people who were not viremic but were anti-GBV-C E2 antibody-positive. Although the mortality rate was higher among the GBV-C “exposed” individuals, the results were not statistically significant. Looking at HIV-infected persons, Lefrere and colleagues reported a significant delay in the rate of CD4+ T cell decline, development of AIDS, and death in 23 HIV-positive individuals with GBV-C viremia compared to 72 HIV-infected people without GBV-C viremia (Lefrère et al., 1999). In that study, HIV-infected individuals who were also GBV-C-positive were compared to HIV-infected individuals who were GBV-C-negative. When these subjects were matched by age, sex, baseline HIV RNA load, and baseline CD4 T cell count, HIV disease progression appeared to be worse in GBV-C-negative subjects.
The interrelationship between HIV and GBV-C continues to be explored, with possible therapeutic aspects of GBV-C infection being examined.